MRT67307

MRT67307 is a dual inhibitor of the IKKε and TBK-1, which mediates the phosphorylation of interferon regulatory factor 3 (IRF3), with IC50 values of 160 and 19 nM when assayed at 0.1 mM ATP in vitro, and also targets ULK1 and ULK2 with high potency (IC50 values of 45 and 38 nM, respectively).

Customer Validation

MRT67307 efficiently inhibits the AKT degradation. IB analysis using WT CD4+ T cells, pretreated for 1 h with a TBK1 inhibitor, MRT67307, of solvent control DMSO and subsequently stimulated for the indicated times with anti-CD3 plus anti-CD28 in the presence of a protein synthesis inhibitor, Cycloheximide.

•Related Small Molecules:

Biological Activity

Protocol

Technical Information

Purity & Documentation

References

Description

MRT67307 is a dual inhibitor of the IKKε and TBK-1, which mediates the phosphorylation of interferon regulatory factor 3 (IRF3), with IC50 values of 160 and 19 nM when assayed at 0.1 mM ATP in vitro, and also targets ULK1 and ULK2 with high potency (IC50 values of 45 and 38 nM, respectively).

MRT67307 actually enhances phosphorylation in IKKα−/− MEFs, the IL-1-stimulated phosphorylation of p105 at Ser933 and RelA at both Ser468 and Ser536. MRT67307 also enhances IL-1-stimulated activation of NF-κB-dependent gene transcription in wild-type MEFs. Treatment of macrophages with MRT67307 leads to an increase in the poly(I:C)- and LPS-stimulated phosphorylation of p105 and RelA and enhanced NF-κB transcriptional activity[1]. MRT67307 (10 μM) is sufficient to reduce phospho-ATG13 to control levels, and in line with the in vitro IC50 values, 10-fold less MRT68921 (1 μM) results in a similar reduction. MRT67307 and MRT68921 inhibit ULK and block autophagy in cells[2]. MRT67307 increases IL-10 production and suppresses proinflammatory cytokine production in macrophages. MRT67307 increases CREB-dependent gene transcription by promoting the dephosphorylation of CRTC3. MRT67307 does not inhibit the brain-specific kinases (BRSKs) and only inhibits the maternal embryonic leucine zipper kinase (MELK) and AMPK itself more weakly[3].

Substrates and kinases are diluted in 50 mM Tris/HCl (pH 7.5), 0.1% 2-mercaptoethanol, 0.1 mM EGTA and 10 mM magnesium acetate. Reactions are initiated with [γ-32P]ATP (2500 c.p.m./pmol) to a final concentration of 0.1 mM and terminated after 15 min at 30°C by the addition of SDS and EDTA (pH 7.0) to final concentrations of 1.0% (w/v) and 20 mM respectively. After heating for 5 min at 100°C and separation by SDS/PAGE, the phosphorylated proteins are detected by autoradiography. MCE has not independently confirmed the accuracy of these methods. They are for reference only.